Department of Pharmacology, Laboratory of Molecular Neuropathology, Soochow University College of Pharmaceutical Sciences, Suzhou, Jiangsu 215123, People's Republic of China.
Mol Neurodegener. 2012 Aug 14;7:40. doi: 10.1186/1750-1326-7-40.
Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson's disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XL and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown.
We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XL more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.
Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-XL functions.
DJ-1/PARK7 基因的突变或缺失是导致早发性帕金森病（PD）隐性形式的原因。野生型 DJ-1 通过多种途径发挥细胞保护作用，防止细胞死亡。最常研究的突变 DJ-1（L166P）将其亚细胞分布转移到线粒体，并使细胞在应激刺激下更容易发生细胞死亡。我们之前报道过，野生型 DJ-1 与 Bcl-XL 结合，并稳定其免受紫外线 B（UVB）照射诱导的快速降解。然而，线粒体 DJ-1（L166P）在死亡刺激下促进细胞死亡的机制在很大程度上尚不清楚。
我们表明，DJ-1（L166P）更容易定位于线粒体，并且与野生型 DJ-1 相比，它与 Bcl-XL 的结合更强。此外，UVB 照射显著促进 DJ-1（L166P）向线粒体的易位和与 Bcl-XL 的结合。DJ-1（L166P）而不是野生型 DJ-1 将 Bax 从 Bcl-XL 解离，从而导致 Bax 在外侧线粒体膜上的富集，并在响应 UVB 照射时促进线粒体凋亡途径。
我们的研究结果表明，野生型 DJ-1 通过差异调节线粒体 Bax/Bcl-XL 功能来保护细胞，而 DJ-1（L166P）则损害细胞。
Zotero 插件
